1. Field of the Invention
This invention relates to novel fused-azacyclic quinoxalinediones that may be employed as excitatory amino acid antagonists. The invention also relates to both a radioimmunossay and enzyme immunoassay for certain fused-azacyclic quinoxalinediones and novel analogs of fused-azacyclic quinoxalinediones employed in such immunoassays.
2. Related Background Art
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acid (EAA) glutamate and aspartate at the N-methyl-D-aspartate (NMDA), the .alpha.-amino-3-hydroxy-5-methyl-4-isoxazole propionate acid (AMPA) receptor, and the kainate receptor. This excitotoxic action is responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma, as well as lathyrism, Alzheimer's, Parkinson's, and Huntington's disease. Several classes of quinoxalinedione derivatives have been disclosed as glutamate (EAA) receptor antagonists. For example, U.S. Pat. No. 4,889,855, generically discloses compounds of the formulae: ##STR1## wherein R.sub.1, R.sub.2 and R.sub.3 are independently H, halogen, CN, NH.sub.2, NO.sub.2, SO.sub.3 H, SO.sub.2 NH.sub.2, and CONH.sub.2. This reference specifically discloses 6-amino, 6-cyano, 5-carbamoyl, 6-nitro, and 5,6-dinitro-7,8,9,10-tetrahydro-2,3-dihydroxybenzo(f)quinoxalines. The reference, however, does not disclose any compounds with an azacycloalkyl fused ring, let alone an N-substituted ring. Nor does the reference disclose or suggest any methods which would allow the preparation of N-substituted azacycloalkyl ring fused compounds. U.S. Pat. Nos. 5,081,123 and 5,308,845, describe similar structures except that there is respectively a hydroxy or alkoxy function at the nitrogen on the quinoxalinedione skeleton. Again, however, these references do not suggest or illustrate any examples of N-substituted fused azacycloalkyl quinoxalinediones.
Among excitatory amino acid receptor antagonists recognized for usefulness in the treatment of disorders are those that block AMPA receptors (Bigge C. F. and Malone T. C., Curr. Opin. Ther. Pat., 1993;951, Rogawski M. A., TiPS 14, 1993;325). AMPA receptor antagonists have prevented neuronal injury in several models of global cerebral ischemia (Li H. and Buchan A. M., J. Cerebr. Blood Flow Metab., 1994;13:933, Nellgard B. and Wieloch T., J. Cerebr. Blood Flow Metab., 1992;12:2) and focal cerebral ischemica (Bulock R., Graham D. I., Swanson S., McCulloch J., J. Cerebr. Blood Flow Metab., 1994;14:466); Xue D., Huang Z.-G., Barnes K., Lesiuk H. J., Smith K. E., Buchan A. M., J. Cerebr. Blood Flow Metab., 1994;14:251. AMPA antagonists have also shown efficacy in models for analgesia (Xu X.-J., Hao J.-X, Seiger A., Wiesenfeld-Hallin Z., J. Pharmacol. Exp. Ther., 1993;267:140), and epilepsy (Namba T., Morimoto K., Sato K., Yamada N., Kuroda S., Brain Res., 1994;638:36; Brown S. E., McCulloch J., Brain Res., 1994;641:10; Yamaguchi S. I., Donevan S. D., Rogawski M. A., Epilepsy Res., 1993;15:179; Smith S. E., Durmuller N., Meldrum B. S., Eur. J. Pharmacol., 1991;201:179) AMPA receptor antagonists have also demonstrated promise in chronic neurodegenerative disorders such as Parkinsonism. (Klockgether T., Turski L., Honere T., Zhang Z., Gash D. M., Kurlan R., Greenamyre J. T., Ann. Neurol., 1993;34(4):585-593.)
Excitatory amino acid receptor antagonists that block nmDA receptors are also recognized for usefulness in the treatment of disorders. nmDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the nmDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson's disease (Klockgether T., Turski L., Ann. Neurol. 1993;34:585-5933), human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (Francis P. T., Sims N. R., Procter A. W., Bowen D. M., Neurochem J. 1993;60(5):1589-1604) and Huntington's disease. (See Lipton S. A., TINS 1993;16(12):527-532; Lipton S. A., Rosenberg P. A., New Eng. J. Med. 1994;330(9):613-622; and Bigge C. F., Biochem. Pharmacol., 1993;45:1547-1561 and references cited therein.) nmDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (Eur. Pat. Appl. 488,959A).
Copending U.S. patent application Ser. No. 08/124,770 discloses glutamate receptor antagonist quinoxalinedione derivatives represented by the formula: ##STR2## wherein A is a 5 to 7 atom containing ring having a nitrogen which may be substituted by hydrogen, alkyl, or CH.sub.2 CH.sub.2 OH. This application does not disclose or suggest compounds having different nitrogen substituents, or the requisite methodology to prepare the same.
Copending U.S. patent application Ser. No. 08/404,400 discloses certain N-substituted fused azacycloalkylquinoxalinediones wherein the N-substituent may be selected from alkylCOOR.sup.3, alkylamine, alkylquanidine, aryl, alkylaryl, COalkyl, COalkylaryl, CSNR.sup.3 alkylaryl, or a common amino acid moiety joined by an amine bond and wherein R.sup.3 is hydrogen, alkyl, or alkylaryl. However, additional derivatives of N-substituted fused azacycloalkylquinoxalinediones that are useful as excitory amino acid antagonists would be desirable. It is also highly desirable to have an accurate manner of assaying N-substituted fused azacycloalkylquinoxalinediones in plasma and in cerebrospinal fluid or brain microdialysate to assist in the study of these compounds in their use as neuroprotective agents.